Process for preparation of 2-chlorophenylglycine derivatives and enantiomerically separation

ABSTRACT

The present invention relates to novel processes and intermediates for the preparation of R(−)-α-2-chlorophenylglycine, S(+)-α-2-chlorophenylglycine, and RS-2-chlorophenylglycine derivatives of formulas I, II and III, respectively. The resulting enantioseparative system was validated in order to evaluate the presence of the enantiomer in pharmaceutical samples. These compounds are found useful as an active ingredient for the pharmaceutical intermediate or as an active ingredient as the tools for delivery of drugs.

BACKGROUND OF THE INVENTION

[0001] 1. Field of the Invention

[0002] The invention relates to novel processes and intermediates forthe preparation of R(−)-α-2-chlorophenylglycine,S(+)-α-2-chlorophenylglycine, and RS-2-chlorophenylglycine derivativesof the formula I, II and III which was synthesized and separated inseveral steps from 2-chlorophenylglycine and camphor sulfonic acid; forthis purpose (+)-camphor-10-sulfonic acid, a chiral ion-pairing reagent,was found to be an essential additive in obtaining a baselineseparation. The resulting enantioseparative system was validated inorder to evaluate the presence of the enantiomer in pharmaceuticalsamples. These compounds are found useful as an active ingredient forthe pharmaceutical synthesis of taxol, taxotere, clopidogrel,chlorfenapyr (Insecticide/Acaricide), AIDS and some antibiotics etc.

[0003] 2. Description of the Prior Art

[0004] Suitable conditions for the enantioseparation were found byvariation of the separation conditions. The influence of addition oforganic solvents like acetonitrile or methanol, and other chiraladditives (camphor-10-sulfonic acid, malic acid and tartaric acid) wasexamined. The addition of an organic modifier resulted in differenteffects on micelle formation, and thereby on the separation. The usedchiral additives did not improve the selectivity. Salami, M.Electrophoresis, vol. 22, pp. 3291-3296 (2001). In the present work thebehavior of the compounds in preparation systems containing camphorsulfonic acid has been studied. While, in the synthesis ofS-(+)-2-chlorophenylglycine indicating the camphor sulfonic acid wasobserved, which caused significant increase of yield in the preparationsystems with mother liquid as re-crystallization and recycle process.This phenomenon is interpreted by the formation of(+)-2-chlorophenylglycine/d-camphor sulfonic acid salt on the motherliquid layer and as a consequence of mixed isomeric mixtures mechanism.Theoretical considerations as well as the identical separation of themixture make plausible the appearance and separation of conformationalenantiomers.

[0005] The S-(+)-2-chlorophenylglycine was synthesized, and itsenantiomers were obtained on a multigram scale in >99% optical purity byoptical resolution of the racemate with the camphor sulfonic acid. Theabsolute configuration of S-(+)-2-chlorophenylglycine was determined byanalysis of the salt with (+)-camphoric sulfonic acid. Since thechirality of the starting material was known, and the relativeconfiguration of compounds were obtained by analysis, the assignment ofthe absolute stereochemistry of the entire series could be made.

[0006] The selectivity of separation of the 2-chlorophenylglycineenantiomers increase with rising concentration of methanol inaqueous-organic mobile phases, pH and temperature. The retentionbehavior of the enantiomers of underivatized phenylglycine was studiedon a Chirobiotic T column packed with amphoteric glycopeptideteicoplanin covalently bonded to the surface of silica gel. The bandprofiles of the less retained L-phenylglycine are symmetrical, but theband profiles of the more strongly retained D-phenylglycine are tailingin all mobile phases tested. The band broadening does not diminish evenat very low concentrations of phenylglycine, so that it cannot beattributed to possible column overload. The analysis of the band profileusing the stochastic theory of chromatography suggests that thebroadening can be attributed to at least two additional chiral centersof adsorption in the stationary phase contributing to the retention ofthe more strongly retained enantiomer in addition to the adsorption ofthe less retained one. This behavior can be explained by the complexstructure of the teicoplanin chiral stationary phase. Jander P,Backovska V, Felinger A. J. Chromatogr. A 2001 Jun. 1;919(1):67-77.

SUMMARY OF THE INVENTION

[0007] In this invention, we prepared and separated various racemic2-chlorophenylglycine containing S-(+)-2-chlorophenylglycine,R-(−)-2-chlorophenylglycine and RS-2-chlorophenylglycine, respectively.A series of racemic 2-chlorophenylglycine having the following formulaare synthesized and separated in the present invention:

[0008] wherein configurational form of isomers are S-(+), R-(−) andracemate. Preferably, configurational form of isomers of2-chlorophenylglycine of the formula I, II and III are enantiomers.Current work details on-going efforts to improve the effectiveness ofthis type of enantiomers. The analytes used in this study includedvarious phenylglycine homologues. In an attempt to increaseenantioselectivity, the effect of solvent, temperature and pH modifierswas evaluated in an aqueous mobile phase containing sulfuric acid.

[0009] S-form of 2-chlorophenylglycine having the following formula wassynthesized and separated by the present invention. R-form of2-chlorophenylglycine having the following formula was synthesized andseparated by the present invention. Enantiomers of 2-chlorophenylglycinehaving the following formula was synthesized and separated by thepresent invention.

BRIEF DESCRIPTION OF THE DRAWINGS

[0010]FIG. 1 (Scheme 1) shows synthetic method of 2-Chlorophenylglycine.

[0011]FIG. 2 (Scheme 2) shows resolution procedures on racemic mixtureof 2-chlorophenylglycine.

[0012] Table. 1 shows the ¹H NMR, IR of S-form of 2-chlorophenylglycine.

DETAILED DESCRIPTION OF THE INVENTION

[0013] In this invention, we prepared and separated various racemic2-chlorophenylglycine containing S-(+)-2-chlorophenylglycine,R-(−)-2-chlorophenylglycine and RS-2-chlorophenylglycine, respectively.A series of racemic 2-chlorophenylglycine having the following formulaare synthesized and separated in the present invention:

[0014] R(−)-α-2-chlorophenylglycine S(+)-α-2-chlorophenylglycineRS-2-chlorophenylglycine wherein configurational form of isomers areS-(+), R-(−) and racemate. Preferably, configurational form of isomersof 2-chlorophenylglycine of the formula I, II and III are enantiomers.Current work details on-going efforts to improve the effectiveness ofthis type of enantiomers. The analytes used in this study includedvarious phenylglycine homologues. In an attempt to increaseenantioselectivity, the effect of solvent, temperature and pH modifierswas evaluated in an aqueous mobile phase containing sulfuric acid.

[0015] S-form of 2-chlorophenylglycine having the following formula wassynthesized and separated by the present invention. R-form of2-chlorophenylglycine having the following formula was synthesized andseparated by the present invention. Enantiomers of 2-chlorophenylglycinehaving the following formula was synthesized and separated by thepresent invention.

[0016] The 2-chlorophenylglycine analogs were synthesized according tothe experiment as below. The enantiomerically pure S-form of2-chlorophenylglycine, R-form of 2-chlorophenylglycine and racemic2-chlorophenylglycine were determined by ¹H-NMR spectroscopy andenantioselectivities were determined by optical rotation. Theenantiomeric excesses are dependent on the reaction temperature,concentration, pH and solvent when the reaction were carried out withthe complex prepared from 2-Chlorobenzaldehyde, ammoniumhydrogencarbonate, and sodium cyanide. The high asymmetric induction inthe reaction can be rationalized by assuming that the reaction proceedsvia the intermediacy of enantiomer shown in Scheme. The enantiomericpurity of the stereoisomers was determined by a high-performance liquidchromatography-chiral stationary phase technique (HPLC-CSP).Accordingly, in one embodiment of the invention, there is provided ancompound according to formula I, II, III as defined below and shown inFIG. 1, said compound containing enantiomeric purity of thestereoisomers.

[0017] 2-Chlorophenylglycine was prepared according to a syntheticmethod depicted in FIG. 1. A solution of 2-chlorobenzaldehyde, ammoniumhydrogencarbonate (NH₄HCO₃; 23.7 g), and sodium cyanide (NaCN; 14.7 g)in 500 ml of methanol and 500 ml water, was stirred at 65-70° C. for 5h. The solution was concentrated and transferred to autoclave and added45% NaOH solution, was refluxed for 4 h at 120° C. The reaction mixturewas added 2 g of active carbon and stir for 10 min. The active carbonwas filtered and the pH of filtrate was adjusted by 50% H₂SO₄ to 7-8.The precipitated was filtrated and washed with water and gave 27 g (58%)of 2-chlorophenylglycine. RS-2-chlorophenylglycine specific rotation.

[0018] A racemic mixture of 2-chlorophenylglycine was prepared accordingto general synthetic procedures. The two enantiomers of2-chlorophenylglycine were resolved by D-camphor sulfonic acid in water.A solution of racemic 2-chlorophenylglycine (60 g) and D-camphorsulfonic acid (80 g) in 360 ml of water, was stirred at 85° C. for 30min. The precipitate S(+)CPG-DSC was filtered and washed with water. Thefiltrate was mother liquid as recycle. The wet S(+)CPG-DSC was dissolvedin 80 ml of water and adjusted to pH 7. The precipitate was filtered andwashed with water, dried to give 12.3 g of S(+)-2-chlorophenylglycine.The filtrate was added to mother liquid and washed with 45% NaOH andconcentrated and then added 70 ml of HCl to regenerate the targetcompound. S(+)-2-Chloro-Phenylglycine, R(−)-2-Chloro-Phenylglycine, andRS-2-Chloro-Phenylglycine were obtained.

[0019] The characterized of prepared process was found to be anessential additive in obtaining a baseline separation, whether pH 7-8adjustment using NaOH solution and H₂SO₄ solution. The color removingusing active carbon, and that the chiral ion-pairing reagent wasD-camphor sulfonic acid.

[0020] A pharmaceutical composition for the synthesis of taxol,taxotere, clopidogrel, chlorfenapyr (Insecticide/Acaricide), AIDS andsome antibiotics or a pharmaceutical acceptable material thereof,S-(+)-2-chlorophenylglycine and R-(−)-2-chlorophenylglycine as an activeingredient in preparation for a pharmaceutically acceptable carrier orthe active ingredient.

[0021] The design and synthesis of novel chiral catalysts for asymmetricreactions continues to be an important and active area of research.While the invention is susceptible of various modifications andalternative constructions, certain illustrated embodiments thereof havebeen shown in the drawings and will be described below in detail. Itshould be understood, however, that there is no intention to limit theinvention to the specific form disclosed, but, on the contrary, theinvention is to cover all modifications, alternative constructions, andequivalents falling within the spirit and scope of the invention asdefined in the claims.

Detailed Description of Experiment

[0022] Materials 2-Chlorobenzaldehyde, ammonium hydrogencarbonate(NH₄HCO₃), sodium cyanide, NaOH, H₂SO₄ and methanol were commercialmaterials. Melting points were determined with a Büchi B-545 meltingpoint apparatus and are uncorrected. All reactions were monitored by TLC(silica gel 60 F₂₅₄). ¹H-NMR: Varian GEMINI-300 (300 MHz) and BruckerAM-500 (500 MHz); δ values are in ppm relative to TMS as an internalstandard. Fourier-transform IR spectra (KBr): Perkin-Elmer 983Gspectrometer. The UV spectra were recorded on a Shimadzu UV-160A.Typical experiments illustrating the general procedures for thepreparation are described below.

EXAMPLE 1 General Synthetic Procedures

[0023] 2-Chlorophenylglycine was prepared according to a syntheticmethod depicted in Scheme 1. A solution of 2-chlorobenzaldehyde,ammonium hydrogencarbonate (NH₄HCO₃; 23.7 g), and sodium cyanide (NaCN;14.7 g) in 500 ml of methanol and 500 ml water, was stirred at 65-70° C.for 5 h. The solution was concentrated and transferred to autoclave andadded 45% NaOH solution, was refluxed for 4 h at 120° C. The reactionmixture was added 2 g of active carbon and stir for 10 min. The activecarbon was filtered and the pH of filtrate was adjusted by 50% H₂SO₄ to7-8. The precipitated was filtrated and washed with water and gave 27 g(58%) of 2-chlorophenylglycine. RS-2-chlorophenylglycine specificrotation +0.16 (C=1, 1N HCl); mp 185.4-186.8° C.

EXAMPLE 2 General Resolution Procedures

[0024] A racemic mixture of 2-chlorophenylglycine was prepared accordingto general synthetic procedures. The two enantiomers of2-chlorophenylglycine were resolved by D-camphor sulfonic acid in water.A solution of racemic 2-chlorophenylglycine (60 g) and D-camphorsulfonic acid (80 g) in 360 ml of water, was stirred at 85° C. for 30min. The precipitate S(+)CPG-DSC was filtered and washed with water. Thefiltrate was mother liquid as recycle. The wet S(+)CPG-DSC was dissolvedin 80 ml of water and adjusted to pH 7. The precipitate was filtered andwashed with water, dried to give 12.3 g of S(+)-2-chlorophenylglycine.[α]=+115.6°, C=1N HCl. The filtrate was added to mother liquid andwashed with 45% NaOH and concentrated and then added 70 ml of HCl toregenerate the target compound. S(+)-2-Chloro-Phenylglycine: specificrotation +114.9 (C=1, 1N HCl); mp 184.4-185.7° C.R(−)-2-Chloro-Phenylglycine: specific rotation −111.5 (C=1, 1N HCl); mp184.9-185.8° C. RS-2-Chloro-Phenylglycine: specific rotation +0.16 (C=1,1N HCl); mp 185.4-186.8° C.

[0025] While there is shown and described the present preferredembodiment of the invention, it is to be distinctly understood that thisinvention is not limited thereto but may be variously embodied topractice within the scope of the following claims. From the foregoingdescription, it will be apparent that various changes may be madewithout departing from the spirit and scope of the invention as definedby the following claims. TABLE 1 The ^(1H NMR), IR of S-form of2-chlorophenylglycine. S-(+)-2-chlorophenylglycine ¹H NMR 7.456 7.4377.429 7.423 7.367 7.357 7.346 7.338 7.330 7.324 7.317 7.311 7.297 7.2915.074 IR 2363.63 1676.19 1633.33 1504.76 1376.19 1047.61 747.61R-(−)-2-chlorophenylglycine ¹H NMR 7.452 7.434 7.426 7.421 7.364 7.3537.343 7.335 7.327 7.320 7.314 7.308 7.294 7.287 5.071 IR 2354.06 1680.951633.33 1504.76 1376.19 747.61 RS-2-chlorophenylglycine ¹H NMR 7.4587.439 7.431 7.424 7.369 7.360 7.348 7.340 7.332 7.326 7.319 7.313 7.3057.298 7.292 5.077 IR 3052.63 2985.64 2612.44 2354.06 1642.85 1576.191533.33 1438.09 1430.09 1347.61 1190.47 1057.14 742.85

We claim:
 1. Process for preparing the 2-chlorophenylglycine isomer ofthe compounds of formula

characterized in that a (+)-camphor-10-sulfonic acid, a chiralion-pairing reagent, was found to be an essential additive in obtaininga baseline separation and recycling from the mother liquid, thereof, thecompounds of formula of 2-chlorophenylglycine isomer wherein stericisomers are R(−)-α-2-chlorophenylglycine (I) andS(+)-α-2-chlorophenylglycine (II). Wherein 2-chlorobenzaldehyde,ammonium hydrogencarbonate, and sodium cyanide in methanol and water wasreacted.
 2. Process for resolution of the enantiomeric isomer of theR(−)-α-2-chlorophenylglycine, S(+)-α-2-chlorophenylglycine fromRS-2-chlorophenylglycine.
 3. A racemic mixture of 2-chlorophenylglycinewas prepared according to general synthetic procedures. The twoenantiomers of 2-chlorophenylglycine were resolved by D-camphor sulfonicacid in water. A solution of racemic 2-chlorophenylglycine and D-camphorsulfonic acid in water, was stirred at 85° C. for 30 min. Theprecipitate S(+)CPG-DSC(S(+)-chlorophenylglycine-d-camphoric sulfonicacid) was filtered and washed with water. The filtrate was mother liquidas recycle. The wet S(+)CPG-DSC was dissolved in water and adjusted topH
 7. The precipitate was filtered and washed with water, dried to giveS(+)-2-chlorophenylglycine. The filtrate was added to mother liquid andwashed with 45% NaOH and concentrated and then added HCl to regeneratethe target compound.
 4. Process according to claim 1, characterized inthat the starting materials are 2-chlorobenzaldehyde, ammoniumhydrogencarbonate, and sodium cyanide.
 5. Process according to claim 1,characterized in that the pH adjustment using NaOH solution and H₂SO₄solution.
 6. Process according to claim 1, characterized in that theremoving the color using active carbon.
 7. Process according to claim 1,characterized in that the chiral ion-pairing reagent was D-camphorsulfonic acid.
 8. Process according to claim 2, characterized in thatthe final resolution isomer is S(+)-α-2-chlorophenylglycine.
 9. Processaccording to claim 2, characterized in that from the mother liquidresolution isomer is R(−)-α-2-chlorophenylglycine.
 10. Process accordingto claim 2, characterized in that the cyclization is carried out in thepresence of pH, temperature and water.
 11. Process according to claim 2,characterized in that the chiral ion-pairing reagent was D-camphorsulfonic acid.
 12. Enantiomeric isomer of theR(−)-α-2-chlorophenylglycine and S(+)-α-2-chlorophenylglycine and theracemic form of RS-2-chlorophenylglycine thereof.
 13. A pharmaceuticalcomposition for the synthesis of taxol, taxotere, clopidogrel,chlorfenapyr (Insecticide/Acaricide), AIDS and some antibiotics or apharmaceutical acceptable material thereof, as an active ingredient inpreparation for a pharmaceutically acceptable carrier or the activeingredient.